KR20210109733A - A pharmaceutical composition comprising loganic acid for preventing or treating cognitive impairment related disease - Google Patents

Abstract

The present invention relates to a composition for preventing or treating cognitive impairment-related diseases, comprising loganic acid isolated from Stachys sieboldii. A compound can be usefully used as a composition or preventing or treating cognitive impairment-related diseases due to an excellent brain cell protection effect. The compound is preferably obtained by chromatographic fractionation from an extract of Stachys sieboldii.

Description

A pharmaceutical composition comprising loganic acid for preventing or treating cognitive impairment related disease, comprising loganic acid

The present invention relates to a pharmaceutical composition for preventing or treating cognitive impairment-related diseases, including rorganic acid.

The brain is the highest central organ of the nervous system of all animals in which nerve cells form a single mass, and is involved in motor functions, sensory information processing functions, language functions, learning and memory functions, homeostasis maintenance, and hormone secretion. Diseases that occur in the brain due to abnormalities in brain function include cognitive impairment, which includes decreased attention, decreased learning ability, decreased memory, and impairment of sensory perception.

Neurodegenerative disease (neurodegenerative disease) is a brain disease that occurs with aging is known to occur due to the accumulation of environmental and genetic factors. It is a collective term for a disease that causes various symptoms as degenerative changes due to gradual and steady death occur in nerve cells of the central nervous system, and is characterized by loss of neural structure and function, including cell damage and memory impairment. Representative examples include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

Glutamate is known to cause neuronal cell loss in the central nervous system and may be involved in neurological diseases such as seizures, Alzheimer's disease, Parkinson's disease, ischemia and spinal cord trauma. In this regard, memantine among Alzheimer's disease drugs blocks glutamate, an excitatory neurotransmitter, and glutamate overstimulates nerves in the brain and causes excessive calcium influx into cranial nerve cells, thereby preventing damage and death of cranial nerves. Memantine is known to prevent this. However, despite the fact that these chemical agents and natural compositions are on the market, an excellent formulation with a certain efficacy has not yet been developed, and in addition, commercially available drugs cause many side effects such as hepatotoxicity, insomnia, high blood pressure, and vomiting. have. Therefore, in cognitive impairment-related diseases and neurodegenerative diseases caused by various causes, it is possible to delay brain cell destruction and aging to protect brain cells, restore cognitive function, and have fewer side effects and prevent the progression of the disease. Development has become an urgent task.

On the other hand, as a prior art related to a composition for the prevention or treatment of cognitive impairment-related diseases, Korean Patent No. 10-2064610 discloses a composition for improving cognitive ability containing choseokjam material and black ginseng material as active ingredients, Korea Registered Patent No. 10-0890179 discloses a composition for the prevention and treatment of cognitive dysfunction-related diseases containing ginseng extract as an active ingredient, and Korean Patent Publication No. 10-2020-0000048 discloses cognitive impairment-related diseases containing chebulanin. A composition for preventing or treating a disease has been disclosed. However, as in the present invention, there is no previous report confirming the preventive or therapeutic effect of rorganic acid for cognitive impairment-related diseases.

Accordingly, the present inventors were able to complete the present invention by confirming that, in the course of researching the components of Choseokjam, in particular, the protective effect of rorganic acid on brain nerve cells was excellent.

Korean Patent Registration No. 10-2064610, Cognitive intelligence improvement composition containing primordia and black ginseng material as active ingredients, registered on January 03, 2020. Korean Patent No. 10-0890179, a composition for the prevention and treatment of cognitive dysfunction-related diseases containing ginseng extract as an active ingredient, registered on March 17, 2009. Korean Patent Application Laid-Open No. 10-2020-0000048, a composition for preventing or treating cognitive impairment-related diseases including chebulanin, January 02, 2020, published.

An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cognitive impairment-related diseases, including rorganic acid isolated from choseokjam ( Stachys sieboldii ).

The present invention relates to a pharmaceutical composition for preventing or treating cognitive impairment-related diseases, including rorganic acid.

The compound may be synthesized according to a conventional method in the art and may be prepared as a pharmaceutically acceptable salt, but is preferably obtained by fractionation by chromatography from an extract of Stachys sieboldii.

The choseokjam is a plant originating from Stachys sieboldii Miq of the family Lamiaceae (Labiatae) of the genus Stachys Linne. Lamiaceae seokjam in the pool Plants in Korea velvet seokjam Pool (S. oblongifolia Benth.), Seokjam Pool (S. sieboldii Miq), dissection jampul (S. japonica var. Hispidula (Hara ), hair seokjam Pool (S.japonica var villosa (Kudo) Ohwi) and others.

The Choseokjam extract is water, C1 to C4 alcohol, or a mixed solvent thereof, and the C1 to C4 alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol and isobutanol. . More preferably, a fraction obtained by extracting choseokjam with alcohol or an aqueous alcohol solution, concentrating and suspending in water, and then fractionating with one or more solvents selected from the group consisting of ethyl acetate, n-butanol, and n-hexane is used.

Water, C1 to C4 alcohol, or a mixed solution thereof used for extraction may be used in an amount of 1 to 100 times the weight of choseokjam used, and it is also possible to repeat the above process 1 to 5 times.

The extraction time of the extract is not particularly limited, but it is preferable to extract within 10 minutes to 1 day, and the extraction method includes all commonly used extraction methods, for example, pressure extraction, immersion (cold-chilling, warm-chilling), ultrasonic extraction, A reflux extraction method and the like can be used, and as an extraction device, a conventional extraction device, an ultrasonic crushing extractor, or a fractionator can be used.

In addition, the extract is formed using the extract itself and the extract, such as the extract obtained from the extraction process, the diluted or concentrated liquid of the extract, the dried product obtained by drying the extract, the prepared or purified product of the extract, or a mixture thereof. All possible formulations of extracts are included.

The chromatography is silica gel column chromatography (silica gel column chromatography), flash column chromatography (flash column chromatography), Sephadex LH-20 column chromatography (sephadex LH-20 column chromatography), RP-18 column chromatography (RP) -18 column chromatography), thin layer chromatography (TLC), medium pressure liquid chromatography, and high performance liquid chromatography (HPLC) may be used, but is not particularly limited thereto .

The cognitive impairment-related disease refers to a disease resulting from a decrease in functions such as memory, spatial perception, judgment, executive function, and language ability, preferably learning disability, memory impairment, forgetfulness, mild cognitive impairment or neurodegenerative disease. It is a disease selected from the group consisting of, and the neurodegenerative disease is a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis, and Creutzfeldt-Jakob disease. However, the present invention is not particularly limited thereto, and any cognitive impairment-related disease caused by various causes may be included.

The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans. In addition, the composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient, for example, starch, microcrystalline cellulose, sucrose or lactose, to the compound of the present invention; It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used. In order to formulate a formulation for parenteral administration, the compound or a pharmaceutically acceptable salt thereof is sterilized and/or adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other treatments It can be prepared as a solution or suspension by mixing it with water with useful substances, and it can be prepared in ampoules or vial unit dosage form.

The pharmaceutical composition comprising the compound disclosed in the present invention as an active ingredient may be administered to mammals such as mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebrovascular injection. The dosage may vary depending on the age, sex, weight, specific disease or pathology to be treated, the severity of the disease or pathology, administration time, administration route, absorption, distribution and excretion rate of the drug, the type of other drugs used, and the prescriber's It will depend on judgment, etc. Dosage determination based on these factors is within the level of the skilled artisan, and dosages generally range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.

In another aspect, the present invention relates to a health functional food for preventing or improving cognitive impairment-related diseases, including rorganic acid.

The health functional food refers to food manufactured or processed using raw materials or ingredients having useful functionality, and includes, for example, health supplements, functional foods, nutritional supplements, supplements, and the like.

The rorganic acid is preferably added in an amount of 0.001% to 50% by weight, more preferably 0.001% to 30% by weight, and most preferably 0.001% to 10% by weight based on the total weight of the health functional food. can be

The health functional food of the present invention includes the form of tablets, capsules, pills and liquids, and the like, and the food to which rorganic acid of the present invention can be added includes, for example, various foods, beverages, gum, tea, vitamins. combination drugs, etc.

The present invention relates to a composition for preventing or treating cognitive impairment-related diseases, comprising rorganic acid isolated from Choseokjam, and the compound is useful as a composition for preventing or treating cognitive impairment-related diseases due to its excellent brain cell protection effect. can be used

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<Example 1. Separation of Loganic Acid from Choseokjam>

2.5 kg of dried roots of Stachys sieboldii were extracted under reflux three times with ethanol at 35±3° C., and then the solvent was removed under reduced pressure to obtain an ethanol extract (100 g). The ethanol extract was suspended in distilled water and fractionated with ethyl acetate and water to obtain each fraction. Among the fractions, the ethylacetate fraction (7.0 g) of sulphate was subjected to silica gel column chromatography (CH ₂ Cl ₂ :MeOH:H ₂ O, 7:1:0.1→5:1:0.1→3:1:0.1→1:1). :0.1→1:2:0.1) to obtain 15 small fractions (FE1-FE15). FE7 in the small fraction was subjected to RP-18 silica gel column chromatography (MeOH:H ₂ O, 2:1→1:1) to obtain rorganic acid (20.0 mg) having the following chemical structure.

¹ H-NMR (CD ₃ OD, 400 MHz): δ 5.20 (1H, d, J = 4.3 Hz, H-1), 7.31 (1H, s, H-3), 3.02 (1H, m, H-5 ), 2.16 (1H, m, H-6a), 1.59 (1H, m, H-6b), 3.92 (1H, m, H-7), 1.79 (1H, m, H-8), 1.95 (1H, m, H-9), 1.01 (3H, d, J = 6.8 Hz, H-10), 4.57 (1H, d, J = 7.9 Hz, H-1′), 3.14 (1H, m, H-2′) ), 3.56 (1H, m, H-3′), 3.29 (1H, m, H-4′), 3.40 (1H, m, H-5′), 3.83 (1H, m, H-6a′), 3.70 (1H, m, H-6b');

¹³ C-NMR (CD ₃ OD, 100 MHz): δ 97.8 (C-1), 152.4 (C-3), 114.4 (C-4), 32.3 (C-5), 42.8 (C-6), 75.3 (C-7), 42.3 (C-8), 46.7 (C-9), 13.6 (C-10), 171.3 (CO), 100.2 (C-1′), 74.9 (C-2′), 78.2 ( C-3´), 71.8 (C-4´), 78.5 (C-5´), 62.9 (C-6´).

<Example 2. Confirmation of brain nerve cell protective activity>

The experiment to confirm the cell viability by inducing neuronal toxicity (glutamate treatment) in HT22 cells has been widely used as an in vitro model for the evaluation of neuroprotective activity. Therefore, in order to confirm the brain nerve cell protective activity of the present invention loganic acid, it was carried out as follows.

HT22 cells were inoculated in a 96-well plate at 4.5×10 ⁴ cells/ml, incubated for 23 hours, and then rorganic acid was added. After 1 hour, 3mM glutamate was treated and the cells were killed by inducing neuronal toxicity by further culturing for 24 hours, and then cell viability was measured by WST assay. As a positive control, trolox was used, and the cell viability measurement results are shown in Table 1 below.

compound Brain nerve cell protective effect (%) rorganic acid (10 μM) 102.3±7.1 Positive control (100 μM) 78.9±4.4

Referring to Table 1, it was confirmed that the compound of the present invention had significantly superior brain neuronal protective effect compared to the positive control, Trolux.

When nerve cells are damaged, normal brain functions cannot be performed, and in particular, brain cells are known not to be remade once damaged, unlike other cells. It was found that it can be usefully used as a preventive and therapeutic agent for cognitive impairment-related diseases.

<Formulation Example 1. Preparation of tablets>

20 g of loganic acid of the present invention was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid, respectively. After adding a 10% gelatin solution to this mixture, it was ground and passed through a 14 mesh sieve. This was dried, and 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate were added thereto, and the resulting mixture was made into tablets.

<Formulation Example 2. Preparation of capsules>

After mixing 100 mg of loganic acid of the present invention, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method and filled in a gelatin capsule to prepare a capsule.

<Formulation Example 3. Preparation of injection>

1 g of rorganic acid of the present invention, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20° C. for 30 minutes.

Claims (6)

A pharmaceutical composition for the prevention or treatment of cognitive impairment-related diseases comprising rorganic acid as an active ingredient. According to claim 1,
The cognitive impairment-related disease is a learning disability, memory impairment, forgetfulness, mild cognitive impairment, and a pharmaceutical composition for the prevention or treatment of cognitive impairment-related diseases, characterized in that selected from the group consisting of neurodegenerative diseases. 3. The method of claim 2,
The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis and Creutzfeldt-Jakob disease. A health functional food for the prevention or improvement of cognitive impairment-related diseases containing rorganic acid as an active ingredient. 5. The method of claim 4,
The cognitive impairment-related disease is a health functional food for the prevention or improvement of cognitive impairment-related diseases, characterized in that it is selected from the group consisting of learning disabilities, memory impairment, forgetfulness, mild cognitive impairment and neurodegenerative diseases. 6. The method of claim 5,
The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, amyotrophic axonal sclerosis and Creutzfeldt-Jakob disease.